Hitachi Chemical Advanced Therapeutics Solutions (HCATS) is proud to be an active contributor to the scientific research and publications surrounding the regenerative medicine industry. To this end, many of our staff collaborate with others in the cell therapy industry to perform primary research or to collaborate on articles that help highlight various issues in the industry.

I recently contributed to an article featured in Nature Biomedical Engineering’s June 2018 issue, which discussed various challenges and aspects of the manufacturing and development process for cell therapy products (CTPs). This article was a collaboration between myself and 15 other contributors from throughout the regenerative medicine industry (including Dr. Robert Preti and Courtney LeBlon, also from HCATS).

You can read the full text of the article in the pages of Nature Biomedical Engineering, vol. 2, June 2018, pages 362-76. Here are a few highlights from the article for your review:

The Top Considerations for Quality Target-Product Profiles

In the article, potency is highlighted as one of the most important metrics to focus on when creating a quality target-product profile (QTPP). As stated in the article:

“Potency should be prioritized early in CTP development because it ultimately confirms CTP utility. Potency is the bar by which key decisions are made, including product-lot release, shelf life, comparability between products manufactured within or between sites, and validation of clinical preparation.”

However, it should be noted that while vital, potency can be difficult to quantify because there are so many components that contribute to the evaluation of a product’s potency—such as purity, the variability between different lots of a cell therapy product, and the complex (yet poorly-understood) mechanisms of action that contribute to a cell therapy product’s efficacy.

There is one more key attribute for any QTPP that should be added to the list of the most important metrics to focus on when creating a QTPP: safety. Safety is the top consideration because, if a product is potent but not safe for the patient, then it might as well not work at all.

Other things to consider include the use, storage, treatment timing, temperature, formulation (if additives are necessary), and dosage of the treatment—though many of these things could be considered part of the “potency” metric.

A prominent section of the article discusses the use of viral transduction and electroporation to modify cell functions. Electroporation involves the use of an electrical field to make the membranes of individual cells more permeable so chemicals or new genetic material can be inserted more readily.

Viral transduction is (as noted byScienceDirect) “the virus-mediated transfer of nonviral genetic material to a recipient cell by a process involving the formation of a hybrid genome in which viral genes are substituted by genes derived from the host chromosome.” To grossly oversimplify this definition, it’s the use of a viral vector to introduce changes to the genetic sequences of a given cell to produce a specific effect on the cell’s function.

Electroporation has its uses for altering cell function—but, as noted by the article, “with the full expectation that only short-lived expression of the new genetic material will occur.”

Viral transduction methods, on the other hand, allow for a longer-lasting, more stable alteration of genetic characteristics in target cells. As stated in the article, “primary cells and stem cells require viral transduction methods, rather than electroporation, to efficiently and stably transfer genetic material.”

The drawback to viral transduction, compared to electroporation, is that it is “a highly variable and expertise-dependent step that requires a flexible manufacturing process with associated high costs.” While these costs could be mitigated somewhat by using smaller amounts of “vector” cells, more time would then be needed to culture the resultant treatment cells.

In the future, however, improved efficiency for cell transfection methods could help improve the scalability and cost of this process.

Strategies for Reducing Cost of Goods in Cell Therapy Manufacturing

The cost of goods (COGs) for a cell therapy product can have an enormous impact on the product’s long-term viability for commercial manufacturing. Right now, the COGs for cell therapy products is becoming easier to see thanks in large part to the release of two U.S. FDA-approved CAR-T cell products in the USA—Kymriah (Novartis) and Yescarta (Gilead). As noted in the article, “new approvals have set initial price points ranging from US$93,000 to US$665,000 per treatment.”

Such high costs make these cell therapies difficult to market in countries with a national healthcare system, but a private system with patients who are willing to pay more might be better able to bear higher costs in the short term. Additionally, healthcare providers who base their payments for treatments based on the effectiveness of the treatment might have an impact on the commercial viability of a treatment.

Being able to reduce the final cost of goods for a cell therapy product can make it easier for the market to bear and expand the list of patients who can afford the treatment. Some strategies for reducing COGs discussed in the article include the use of induced pluripotent stem cells (iPSCs) and similar autologous cells to mitigate cell rejection issues, optimizing the preservation and supply chain management of therapy products, and finding ways to manage direct or indirect manufacturing costs.

The Gap Between Clinical Trial Testing and Post-Trial Patient Loads Remains a Challenge

Towards the end of the article, there is an issue discussed that plagues many cell therapy products: The procedures that the developer established for late stage clinical trial testing prove insufficient to the task of managing a post-clinical-trial patient load. Instead of achieving commercial scale, these products flounder because they’re unable to fulfill the four key attributes of a development by design (DbD) process:

Quality

Cost of Goods Sold

Scalability

Sustainability

Many of these processes rely too much on slow and high-cost manual processing methods that introduce high risk of error—leading to batch rejections and other issues that delay production and increase costs. Manual procedures might work for limited-scale testing but result in the rapid overload of manufacturing capacity when thousands of doses have to be made each year.

Here, automation can provide the key to meeting issues of quality, scalability, sustainability, and cost of goods by increasing consistency, removing the risk of human error, and increasing manufacturing throughput. Additionally, diversifying supply chains whenever possible can help to prevent shortages if one supplier becomes unavailable for any reason.

Creating the roadmap to achieving commercial viability can be difficult, requiring an in-depth analysis of your manufacturing process and needs. If you need more information about achieving commercial viability for your cell therapy products, please read chapter one ofThe Road to Manufacturing Commercially Viable Cell Therapies.

For the full text of the Nature Biomed article, you can download the PDF of the article at the link below:

David Smith, PhD, Associate Director, Head of Innovation & Engineering

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